The goal of this project is to study the response of the kidney to fractionated irradiation, and the interaction of this irradiation with chemotherapy agents. Late damage to nonproliferating normal tissues is a major limiting factor in radiotherapy, but there is a paucity of information on late tissue damage from fractionated radiotherapy and on the effects of drug-radiation interaction in such tissues. Radiation nephritis has been reported in both pediatric and adult radiotherapy, and after total body irradiation (TBI) and bone marrow transplantation. The data from these renal tolerance studies will provide the basis for a general model for the late normal tissue effects of radiation and chemo- radiotherapy.
The specific aims of the project can be divided into three groups. 1) Studies of fractionated external beam radiotherapy. a) What is the tolerance of the kidney to multiple small radiation fractions per day, and is the relationship compatible with the linear-quadratic model? b) What is the rate of repair of sublethal damage after small radiation fractions? c) What is the radiation tolerance of the kidney for low dose rate irradiation? d) How does renal tolerance depend on age at irradiation? 2) Radiation nephritis after TBI and bone marrow transplant. a) How does the radiation nephritis seen after TBI and bone marrow transplantation depend on the fractionation and dose rate of the TBI? b) How does this nephritis depend on the drugs used for conditioning and immunosuppression? 3) Studies of the interaction of renal irradiation and chemotherapy. a) How does organ damage caused by drug-TBI combinations affect the pharmacokinetics of drugs that are used after transplantation? b) How does treatment with nephrotoxic chemotherapeutic agents affect tolerance to subsequent renal radiation? c) How does treatment with nephrotoxic agents affect the development of nephritis from previous renal irradiation?

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National Cancer Institute (NCI)
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Radiation Study Section (RAD)
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Medical College of Wisconsin
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Cohen, Eric P; Bedi, Manpreet; Irving, Amy A et al. (2012) Mitigation of late renal and pulmonary injury after hematopoietic stem cell transplantation. Int J Radiat Oncol Biol Phys 83:292-6
Moulder, John E; Cohen, Eric P; Fish, Brian L (2011) Captopril and losartan for mitigation of renal injury caused by single-dose total-body irradiation. Radiat Res 175:29-36
Lenarczyk, Marek; Cohen, Eric P; Fish, Brian L et al. (2009) Chronic oxidative stress as a mechanism for radiation nephropathy. Radiat Res 171:164-72
Cohen, Eric P; Fish, Brian L; Irving, Amy A et al. (2009) Radiation nephropathy is not mitigated by antagonists of oxidative stress. Radiat Res 172:260-4
Cohen, Eric P (2008) HIPAA threatens clinical research. Ann Diagn Pathol 12:311-2
Cohen, Eric P; Irving, Amy A; Drobyski, William R et al. (2008) Captopril to mitigate chronic renal failure after hematopoietic stem cell transplantation: a randomized controlled trial. Int J Radiat Oncol Biol Phys 70:1546-51
Cohen, Eric P; Fish, Brian L; Sharma, Mukut et al. (2007) Role of the angiotensin II type-2 receptor in radiation nephropathy. Transl Res 150:106-15
Moulder, John E; Cohen, Eric P (2007) Renal dysfunction after total body irradiation: dose-effect relationship: in regard to Kal and van Kempen-Harteveld (Int J Radiat Oncol Biol Phys 2006;65:1228-1232). Int J Radiat Oncol Biol Phys 67:319;author reply 319-20
Moulder, J E; Fish, B L; Cohen, E P (2007) Treatment of radiation nephropathy with ACE inhibitors and AII type-1 and type-2 receptor antagonists. Curr Pharm Des 13:1317-25
Moulder, John E; Cohen, Eric P (2007) Future strategies for mitigation and treatment of chronic radiation-induced normal tissue injury. Semin Radiat Oncol 17:141-8

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